1. Field of the Invention
This invention relates to the fields of biochemistry and immunology, and to biological materials for the suppression of immunological reactions. More specifically, this invention relates to the inhibition of the production of leukocyte derived cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) in humans and mammals. Additionally, this invention relates to a method of inhibiting the production of cytokines to arrest or alleviate certain disease and inflammatory states.
2. Art Background
The lymphocytes or white blood cells in the animal body come in two types, B-cells and T-cells. The B-cells produce antibodies in the form of immunoglobulins that bind onto invading organisms while the T-cells produce the lymphokines or cytokines which are responsible for turning B-cells on and off.
Phagocytes important in immunology are polymorphonuclear leukocytes (e.g. neutrophils) and mononuclear phagocytes (e.g. monocytes and macrophages). Phagocyte hypofunction is a cause of recurrent pyogenic infection. To combat pyogenic infection, neutrophils and monocytes respond to chemotactic factors by moving toward the source of infection, where they ingest microorganisms and kill them.
More particularly, a main function of polymorphonuclear leukocytes and monocyte is to kill bacteria and other infectious agents by phagocytosis. The first stage in the ingestion and digestion of a particulate substance by these cells involves the process of bringing the cells and the particles together, usually through chemotaxis. This response is an essential part of host defense against infection. The extensive migration and activity of these cell is manifested by inflammation at the site of injury or invasion of the host.
It is well known that the growth of normal lymphocytes is dependent not only on contact with an antigenic substance or a mitogen, but also on the presence of certain factors known as lymphokines or cytokines.
The known types of lymphokines include IL-2, B-cell factors, macrophage activation factor (MAF), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-3 (IL-3), Interleukin-6 (IL-6), Colony Stimulating Factor (CSF), Tumor Necrosis Factor (TNF), and Gamma Interferon. All of these factors are secreted by white blood cells and are collectively known as cytokines.
Monocytes can be stimulated by various agents, such as LPS (lipopolysaccharides), to produce certain cytokines including TNF, IL-1 and IL-6. LPS contains a polysaccharide and a lipid A part. Polysaccharides such as .beta.1-3 glucans and blocks of .beta.1-4 D-mannuronic acid have been reported to stimulate monocytes to produce cytokines. Certain cytokine stimulating materials are described in our copending patent application, Ser. No. 07/676,102, filed Mar. 27, 1991 entitled DIEQUATORIALLY BOUND .beta.-1,4 POLYURONATES AND USE OF SAME FOR CYTOKINE STIMULATION.
The present invention relates generally to mammalian cytokines, and particularly to the inhibition of production of biologically active mammalian IL-1, IL-6 and TNF. Interleukin-1 is the designation given to a family of polypeptides, released by macrophages and certain other cell types in response to immunogenic and traumatic stimulation, which have a primary role in initiating host response to injury and infection. These cytokines have been associated with a complex spectrum of biological activities. Specifically, IL-1 is a primary immunostimulatory signal capable of inducing thymocyte proliferation via induction of Interleukin-2 release, and of stimulating proliferation and maturation of B lymphocytes. In addition, IL-1 has been linked with prostaglandin production, induction of fever, inflammatory conditions and promotion of wound healing. Recently, both IL-1 and IL-6 have been implicated as important mediators of septic shock (Ohlsson et al., Nature 348, 550-557, 1990; Starnes et al., J. Immunol. 145, 4185-4191, 1990).
Among other activities attributed to IL-1 and other leukocyte derived cytokines is the promotion of leukocyte adherence and the inhibition of neutrophil chemotaxis, both directly contributing to disease and inflammation syndromes.
TNF has been demonstrated to have a variety of wide ranging effects on various cells and tissues in the body during the inflammatory response. TNF has been implicated as a mediator in the pathogenesis of septic shock (Waage, A., A. Halstensen, and T. Espevik, "Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease", Lancet:355 (1987). Thus, the ability to selectively inhibit the production of TNF is highly desirable. Agents which can selectively inhibit the production of TNF are useful therapeutics for limiting inflammatory and degenerative diseases.
Leukocyte response to an acute inflammatory stimulus involves a complex series of events, including adherence to endothelium near the stimulus. Inhibition of cytokine production can be expected to reduce the degree of inflammation seen in conditions, such a septic shock and adult respiratory distress syndrome.
The inhibition of IL-1, IL-6, TNF, and other leukocyte derived cytokines is also of benefit in controlling, reducing, and alleviating many of these conditions, including immunostimulation which causes tissue rejection and certain autoimmune disorders, as well as inflammation. Little is known, however, about the structural requirements of compositions for optimal immunostimulation and suppression thereof. In light of the desirability of inhibiting the activity of IL-1 and TNF and the activity of other leukocyte derived cytokines and the ease with which inhibition can be detected in vitro, there exists a need in the art for inhibitors of IL-1, TNF, and other cytokines, wherein the inhibitors are acceptable for in vivo administration.